Chronic kidney disease (CKD) is defined as persistent
kidney damage accompanied by a reduction in the glomerular filtration
rate (GFR) and the presence of albuminuria. The prevalence of CKD has
steadily increased over the past two decades, and was reported to affect
over 13% of the U.S. population in 2004.1 In 2009, more than
570,000 people in the United States were classified as having end-stage
renal disease (ESRD), including nearly 400,000 dialysis patients and
over 17,000 transplant recipients.2 A patient is determined
to have ESRD when he or she requires replacement therapy, including
dialysis or kidney transplantation. The rise in incidence of CKD is
attributed to an aging populace and increases in hypertension (HTN),
diabetes, and obesity within the U.S. population. CKD is associated with
a host of complications including electrolyte imbalances, mineral and
bone disorders, anemia, dyslipidemia, and HTN. It is well known that CKD
is a risk factor for cardiovascular disease (CVD), and that a reduced
GFR and albuminuria are independently associated with an increase in
cardiovascular and all-cause mortality.3,4

HTN has been reported to occur in 85% to 95% of patients with CKD (stages 3-5).5
The relationship between HTN and CKD is cyclic in nature. Uncontrolled
HTN is a risk factor for developing CKD, is associated with a more rapid
progression of CKD, and is the second leading cause of ESRD in the U.S.6,7
Meanwhile, progressive renal disease can exacerbate uncontrolled HTN
due to volume expansion and increased systemic vascular resistance.
Multiple guidelines discuss the importance of lowering blood pressure
(BP) to slow the progression of renal disease and reduce cardiovascular
morbidity and mortality.8-10 However, in order to achieve and
maintain adequate BP control, most patients with CKD require
combinations of antihypertensive agents; often up to three or four
medication classes may need to be employed.11

Pathophysiology

Hypertension is one of the leading causes of CKD due to
the deleterious effects that increased BP has on kidney vasculature.
Long-term, uncontrolled, high BP leads to high intraglomerular pressure,
impairing glomerular filtration.12,13 Damage to the
glomeruli lead to an increase in protein filtration, resulting in
abnormally increased amounts of protein in the urine (microalbuminuria
or proteinuria).12,13 Microalbuminuria is the presentation of
small amounts of albumin in the urine and is often the first sign of
CKD. Proteinuria (protein-to-creatinine ratio ≥200 mg/g) develops as CKD
progresses, and is associated with a poor prognosis for both kidney
disease and CVD.3,4,14

As discussed previously, the relationship between CKD and
HTN is cyclic, as CKD can contribute to or cause HTN. Elevated BP leads
to damage of blood vessels within the kidney, as well as throughout the
body. This damage impairs the kidney’s ability to filter fluid and waste
from the blood, leading to an increase of fluid volume in the
blood—thus causing an increase in BP.

Staging of CKD

The estimated GFR, which helps clinicians determine how
well the kidneys are filtering waste, is used in the staging of CKD. The
National Kidney Foundation defines CKD as either kidney damage,
identified by markers in the urine or blood or by imaging, with or
without changes in the GFR, or a GFR <60 mL/min/1.73 m2 for a minimum of 3 months.9TABLE 1 depicts the staging criteria as determined by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines.9

Goals of Therapy

Patients with nondiabetic and diabetic CKD should have a target BP goal of <130/80 mmHg.8-10
Ultimately, the rationale for lowering BP in all patients with CKD is
to reduce both renal and cardiovascular morbidity and mortality.
Maintaining BP control and minimizing proteinuria in patients with CKD
and HTN is essential for the prevention of the progression of kidney
disease and the development or worsening of CVD.8,9

Recent literature suggests that BP targets in diabetic and
nondiabetic CKD may need to be individualized based on the presence of
proteinuria. Some trials have failed to show a reduction in
cardiovascular or renal outcomes in diabetic and nondiabetic patients
with CKD when a BP target of <130/80 mmHg is achieved compared to
lowering BP to <140/90 mmHg.15,16 However, patients who
have proteinuria are less likely to experience a decline in renal
function, kidney failure, or death when the lower BP target is achieved.15,17
It is likely that future guidelines may include a lower BP goal,
<130/80 mmHg, for patients with proteinuria, but maintain a goal of
<140/90 mmHg for patients without proteinuria.

Treatment

Agents that not only lower BP but also reduce proteinuria
are recommended as first-line therapy for most patients with CKD and
HTN; data indicate there may be significant long-term benefits in both
cardiovascular and renal outcomes when proteinuria is decreased.9
Several classes of antihypertensive agents may have a role in the
treatment of CKD and HTN. Agents that target the
renin-angiotensin-aldosterone system (RAAS), such as
angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor
blockers (ARBs), are generally considered first-line antihypertensive
therapy for this patient population.8,9,18TABLE 2
provides guidance on recommended antihypertensive agents for patients
with CKD with or without diabetes and with or without proteinuria.

ACE Inhibitors or ARBs: Studies have shown
that antihypertensive agents that target the renin-angiotensin system
prevent kidney decline more so than other agents, even when achieving
similar BP goals.19 These results were found primarily in
patients with proteinuria, whereas the benefit was less substantial for
those without proteinuria. Based on these findings, guidelines recommend
ACE inhibitor or ARB therapy as first-line treatment for those with
diabetes or those presenting with nondiabetic kidney disease, HTN, and
proteinuria. Data indicate that ACE inhibitors and ARBs are equally
effective in lowering BP and reducing proteinuria.20 A recent
meta-analysis suggests that ACE inhibitor therapy may provide superior
benefit over ARB therapy for the treatment of HTN due to a 10% reduction
in all-cause mortality.21 These results were determined for
patients with HTN and did not apply to patients with additional
comorbidities such as CKD. Therefore, selection of one agent over
another will depend on patient-specific factors such as potential for
side effects and cost. Treatment with both an ACE inhibitor and an ARB
is not recommended, as this combination has been shown to worsen kidney
function. Combination ACE inhibitor and ARB therapy did not reduce
cardiovascular mortality or morbidity in comparison to monotherapy of an
ACE inhibitor.20,21

ACE inhibitors and ARBs are generally well tolerated. ACE
inhibitors may cause a dry cough, which unfortunately often requires a
change in therapy. ARBs are not associated with dry cough. Angioedema is
very rare; however, patients started on ACE inhibitors or ARBs should
be informed of the signs and symptoms that may present with angioedema.
Inform patients that angioedema is unlikely, but if they experience
swelling in their face (often including the eyelids) and/or extremities,
they should discontinue treatment and seek medical attention
immediately.18

Thiazide vs. Loop Diuretics:For
patients without proteinuria, a preferred first-line therapy has not
been clearly established, and other agents, such as a thiazide, may be
considered. Patients with CKD and HTN often experience fluid retention
or fluid overload. As a result, diuretics are often necessary in their
treatment regimen. Thiazides are recommended for patients with CKD
stages 1 to 3 (GFR ≥30 mL/min), and have been established as effective
agents for BP and CVD risk reduction.22 Loop diuretics are
recommended for patients with CKD stage 4 or 5 (GFR <30 mL/min), as
they have been shown to be more effective in reducing extracellular
fluid volume in patients with severely reduced GFR.18 However, the long-term effect of loop diuretics on cardiovascular outcomes has not been clearly established.23

Thiazide diuretics (chlorthalidone, hydrochlorothiazide)
and loop diuretics (bumetanide, furosemide, torsemide) all cause
hyperuricemia (increased urination). This increase in fluid loss may
lead to electrolyte imbalance. It is important for patients on these
agents to have their electrolytes monitored to ensure they do not
experience electrolyte abnormalities such as hyperkalemia or
hypomagnesemia. Orthostatic hypotension may occur in response to any
antihypertensive agents; however, it is common with diuretics. It is
important to counsel patients initiating diuretic therapy on the need to
rise slowly from a sitting or lying-down position.24,25

Calcium Channel Blockers:Calcium channel blockers (CCBs) are considered second- or third-line therapy in the treatment of HTN in patients with CKD.8,9
While there may be no difference in the effect on BP lowering between
nondihydropyridine CCBs (ND-CCBs; e.g., diltiazem, verapamil) and
dihydropyridine CCBs (e.g., amlodipine, nifedipine), ND-CCBs have been
shown to significantly reduce proteinuria either when used alone or in
combination with an ACE inhibitor or an ARB.26 Because of
their potential to reduce proteinuria, in addition to their
antihypertensive effects, ND-CCBs should be considered as second- or
third-line therapy in patients with diabetic CKD or nondiabetic CKD with
proteinuria. Dihydropyridine CCBs can be used as second-line agents in
patients with nondiabetic CKD without proteinuria. Common adverse
effects include edema and constipation with ND-CCBs (especially
verapamil) and flushing and peripheral edema with dihydropyridine
agents.18

Aldosterone Antagonists:Aldosterone
plays a severely deleterious role in the progression of CKD. Aldosterone
receptor antagonists (e.g., spironolactone, eplerenone) may have a
place in the role of CKD therapy when BP goals have not been achieved
with first- and second-line therapy. These agents have shown in human
trials to provide a reduction in proteinuria when added to an ACE
inhibitor or ARB.27,28

Aldosterone antagonists are potassium-sparing diuretics,
which increase the risk for hyperkalemia, particularly if taken with an
ACE-inhibitor or ARB. It is important for patients initiated on
potassium-sparing diuretics to have their potassium levels checked to
ensure they do not experience electrolyte abnormalities. Symptoms of
hyperkalemia include heart arrhythmia and severe muscle weakness.
Unfortunately, hyperkalemia may present asymptomatically, which
underscores the importance of monitoring.18,27

Renin Inhibitor:Aliskiren is the
only renin inhibitor currently available on the market. It is indicated
for the treatment of HTN as monotherapy or as combination therapy with
valsartan. Recent data from the ALTITUDE trial have lead to the
contraindication of its use with ACE inhibitors or ARBs in patients with
diabetes or renal impairment (GFR <60 mL/min) due to the increased
risk for renal impairment, hypotension, and hyperkalemia.29
Aliskiren can be considered if the patient cannot take an ACE inhibitor
or an ARB; however, its use cannot be recommended in patients with stage
4 or 5 renal failure.30

Beta-Blockers: Data that evaluate the effect of beta-blockers on the progression of CKD and proteinuria are limited.27 While beta-blockers are not included in TABLE 2,
these agents can be considered as second- or third-line therapy if the
patient has a compelling indication for a beta-blocker such as coronary
artery disease or chronic heart failure.18

Nonpharmacologic Recommendations

Chronotherapy: This type of therapy takes
into consideration circadian BP patterns, and institutes administration
of antihypertensive medication in respect to the daily patterns, moving
away from administration of all antihypertensive medications in the
morning. Trials have demonstrated improved 24-hour BP control in
patients administering CCBs in the evening rather than in the morning.31,32
Additional studies have identified benefit from nighttime
administration of other antihypertensive medications such as ACE
inhibitors or ARBs.33,34 Chronotherapy may warrant some
consideration for those unable to achieve their BP goal when
administering all antihypertensive agents in the morning. If patients
are on more than two antihypertensive agents, it may be appropriate to
administer two agents in the morning and the additional agents in the
evening.

Lifestyle Modification:Increased physical activity, weight loss, and dietary modifications are recommended for all patients with HTN.8
Lifestyle modification remains a critical component of therapy for HTN,
regardless of whether patients require medications to achieve their BP
goal. The Dietary Approaches to Stop Hypertension (DASH) diet emphasizes
an increased consumption of fruits and vegetables, inclusion of low-fat
dairy and lean protein, and a restriction of saturated fats; this meal
plan has been shown to significantly lower systolic BP nearly equivalent
to the reduction achieved by antihypertensive monotherapy.35 In addition, decreasing sodium and alcohol intake has been established as an effective intervention towards decreasing BP.8
Initiating these healthy dietary practices while increasing daily
activity augments the benefit received from anti-hypertensive therapy
and can play an essential role in achieving BP goals.

Summary

The interrelationship of CKD and HTN leads to further
emphasis on the importance of achieving BP control and decreasing
proteinuria, if present. Agents that reduce proteinuria in addition to
BP are generally first line, but patients may often require three to
four antihypertensive agents in order to achieve their goals and
minimize their risk for CVD and ESRD. In addition, healthy lifestyle
modifications should always be considered as a vital component of any
antihypertensive therapy regimen.